System and method for ultrasonic bladder therapeutic agent delivery

ABSTRACT

A catheter for ultrasonic-driven bladder therapeutic agent delivery, including: a tube having a proximal expandable portion and a distal end, and at least one transducer sleeve accommodating at least one ultrasound transducer mounted on the tube between the proximal expandable portion and the distal end.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority from U.S. ProvisionalPatent Application No. 62/651,194 filed on Apr. 1, 2018, entitled“SYSTEM AND METHOD FOR ULTRASONIC BLADDER THERAPEUTIC AGENT DELIVERY”.

This application is related to U.S. patent application Ser. No.15/561,733 filed on Sep. 26, 2017, entitled “ULTRASONIC URINARY BLADDERDRUG DELIVERY”.

The contents of the above applications are incorporated by reference asif fully set forth herein in their entirety.

FIELD OF THE INVENTION

The present invention, in some embodiments thereof, relates to acatheter for bladder therapeutic agent delivery and, more particularly,but not exclusively, to an ultrasonic-driven bladder therapeutic agentdelivery.

BACKGROUND

Intravesical therapy of the urinary bladder involves the bladder innersurface which is covered with transitional epithelium lining calledurothelium, and glycosaminoglycans (GAG) units found on the urothelium.Both the urothelium and the GAG units may function as an importantbarrier to toxins and waste found in the urine, giving the bladder wallits low permeability characteristic. However, this compact and tightbarrier may also restrict effective penetration of therapeutic agentsdelivered into the bladder during intravesical treatments. Sometherapeutic molecules may not penetrate the bladder barrier at all.

Ultrasound cavitation is a mechanism by which acoustic waves canincrease tissue permeability. Cavitation bubbles collapse on the tissueswith high energy and open up pores in the tissues, which result in theincreased permeability of the tissues to therapeutic agents.

The foregoing examples of the related art and limitations relatedtherewith are intended to be illustrative and not exclusive. Otherlimitations of the related art will become apparent to those of skill inthe art upon a reading of the specification and a study of the figures.

SUMMARY

The following embodiments and aspects thereof are described andillustrated in conjunction with systems, tools and methods which aremeant to be exemplary and illustrative, not limiting in scope.

According to an aspect of some embodiments of the present inventionthere is provided a catheter for ultrasonic-driven bladder therapeuticagent delivery, the catheter includes: a tube, two or more expandableportions mounted on the tube, one or more ultrasound transducers mountedon the tube between the two or more expandable portions, and atransducer sleeve disposed between the two or more expandable portionsand accommodating the one or more transducers. According to someembodiments the transducer sleeve and the expandable portions include asingle balloon. In some embodiments, the expandable portion comprises astent.

According to some embodiments the maximal cross-sectional area of thetransducer sleeve at an expanded state is smaller than the maximalcross-sectional area of any one of the expandable portions at least attheir greatest circumference. According to some embodiments of theinvention at least one of the expandable portions is spheroid and atleast one of the expandable portions and the tube are concentric.According to some embodiments of the invention at least one of theexpandable portions and the transducer are concentric.

According to some embodiments of the invention the tube includes atleast one fluid port located within a lumen of at least one of theexpandable portions and/or at least one fluid port along its length thatopens to a lumen of a bladder. The port is configured to supply fluidinto the lumen of the bladder and/or evacuate fluid out of the bladder.

According to some embodiments of the invention the transducer iselevated from a surface of the tube so that to define a gap between thetransducer and the surface of the tube. According to some embodiments ofthe invention the greatest circumference of the transducer sleeve isless than 50% of the greatest circumference of at least one expandableportion and/or the inflation pressure of the transducer sleeve isgreater than the inflation pressure of the expandable portions.According to some embodiments of the invention the tube includes one ormore conduits that supply therapeutic fluid via the port. According tosome embodiments of the invention the tube includes one or more conduitsthat supply gassed fluid via the port. According to some embodiments ofthe invention the tube includes one or more conduits that supply fluidvia the port.

According to some embodiments of the invention the transducer isconfigured to form cavitations in the gassed therapeutic fluid.

According to an aspect of some embodiments of the present inventionthere is provided a catheter for ultrasonic-driven bladder therapeuticagent delivery, the catheter includes a tube, having a proximal portionand a distal end, a proximal expandable portion mounted on the proximalportion of the tube, one or more transducers mounted on the tube betweenthe proximal expandable portion and the distal end, and a transducersleeve between the proximal expandable portion and the distal endaccommodating the one or more transducers. In some embodiments, one ormore of the expandable portions comprises a balloon.

According to some embodiments of the invention the balloon is toroidaland/or configured to inflate distally towards the distal end. Accordingto some embodiments of the invention the tube includes at least onefluid port along its length that opens to a lumen of a bladder and/or islocated between the transducer and the balloon. According to someembodiments of the invention the port is configured to supply fluid intothe lumen of the bladder and/or evacuate fluid out of the bladder.

According to some embodiments of the invention the greatestcircumference of the transducer sleeve is less than 50% of the greatestcircumference of the balloon. According to some embodiments a volume isdefined between the transducers and the transducer sleeve. According tosome embodiments the inflation pressure of the transducer sleeve isgreater than the inflation pressure of the balloon. According to someembodiments of the invention the tube includes one or more conduits thatsupply therapeutic fluid via the port.

According to an aspect of some embodiments of the present inventionthere is provided a method for treating a bladder using a catheter forultrasonic-driven bladder therapeutic agent delivery including:inserting a distal expandable portion of the catheter into the bladdervia a urethra, expanding the expandable portion, supplying therapeuticfluid into the bladder through at least one therapeutic fluid port inthe catheter, advancing the catheter in the bladder and inserting aproximal expandable portion of the catheter into the bladder, expandingthe proximal expandable portion and trapping the therapeutic fluidbetween the distal expandable portion and the proximal expandableportion, and applying ultrasound to form cavitation in the therapeuticfluid. In some embodiments, the method for treating a bladder using acatheter for ultrasonic-driven bladder therapeutic agent deliverycomprises supplying of therapeutic fluid into the bladder through atleast one therapeutic fluid port in the catheter after stopping to emitultrasound energy.

According to some embodiments of the invention the method includessupplying the therapeutic fluid through a port between the expandableportions. According to some embodiments of the invention the therapeuticfluid is gaseous therapeutic fluid.

According to an aspect of some embodiments of the present inventionthere is provided a method for treating a bladder using a catheter forultrasonic-driven bladder therapeutic agent delivery including:inserting a distal expandable portion of the catheter into the bladdervia a urethra, expanding the expandable portion, supplying gassed fluidinto the bladder through at least one fluid port in the catheter,emitting ultrasound energy and forming cavitations in the gassed fluid,draining the bladder content, supplying therapeutic fluid into thebladder through at least one therapeutic fluid port in the catheter, andemitting ultrasound energy and forming cavitations in the therapeuticfluid.

According to some embodiments of the present invention the methodincludes draining and flushing the bladder with saline prior tosupplying the gassed fluid into the bladder.

According to some embodiments the method includes stopping emittingultrasound energy during the draining of the bladder content and/or thesupplying of the therapeutic fluid into the bladder through at least onetherapeutic fluid port in the catheter.

According to an aspect of some embodiments of the present inventionthere is provided a catheter for ultrasonic-driven bladder therapeuticagent delivery, including: a tube having a proximal expandable portionand a distal end; and at least one transducer sleeve accommodating atleast one ultrasound transducer mounted on the tube between the proximalexpandable portion and the distal end.

According to an aspect of some embodiments of the present inventionthere is provided a catheter wherein at least one expandable portion isexpandable inside a bladder from a contracted state to an expanded stateat which the expandable portion is urged against the bladder wall toform a sealed volume within the bladder between the expandable portionand a trigone area of said bladder.

In some embodiments, the catheter includes at least one additionalexpandable portion, wherein the transducer sleeve is disposed betweenthe proximal and said at least one additional expandable portion. Insome embodiments, the transducer sleeve and at least one of theexpandable portions are in fluid communication.

In some embodiments, the maximal cross-sectional area of the transducersleeve at an expanded state is smaller than the maximal cross-sectionalarea of any one of the expandable portions at least at their greatestcircumference. In some embodiments, at least one of the expandableportions is spheroid.

In some embodiments, at least one of the expandable portions and thetube are concentric. In some embodiments, at least one of the expandableportions and the transducer are concentric. In some embodiments, thetube comprises at least one fluid port located within a lumen of atleast one of the expandable portions.

In some embodiments, the tube comprises at least two fluid ports influid communication with the lumen of the transducer sleeve and whereinfluid flow is maintained between the ports. In some embodiments, thetransducer is positioned between the ports.

In some embodiments, the tube comprises at least one therapeutic fluidport along its length that opens to a lumen of a bladder. In someembodiments, the catheter includes a blind tip at the distal end,wherein the at least one therapeutic fluid port is positioned along thecircumference of the tip. In some embodiments, the transducer iselevated from a surface of the tube so that to define a gap between thetransducer and the surface of the tube.

In some embodiments, the catheter comprises at least one spacerpositioned on the tube and wherein the transducer is mounted on the atleast one spacer. In some embodiments, the greatest circumference of thetransducer sleeve is less than 50% of the greatest circumference of atleast one expandable portion. In some embodiments, the tube comprisesone or more conduits that supply fluid via said therapeutic fluid port.

In some embodiments, at least one expandable portion is toroidal. Insome embodiments, at least one expandable portion is configured toinflate distally towards the distal end. In some embodiments, thecatheter comprises at least one fluid port located between thetransducer and at least one expandable portion.

In some embodiments, an expanded state a volume is defined between thetransducer and the transducer sleeve.

According to an aspect of some embodiments of the present inventionthere is provided a method for treating a bladder using a catheter forultrasonic-driven bladder therapeutic agent delivery including:inserting a distal expandable portion of the catheter into the bladdervia a urethra, expanding the expandable portion, supplying therapeuticfluid into the bladder through at least one therapeutic fluid port inthe catheter, advancing the catheter in the bladder and inserting aproximal expandable portion of the catheter into the bladder, expandingthe proximal expandable portion and trapping the therapeutic fluidbetween the distal expandable portion and the proximal expandableportion, and forming cavitations in the therapeutic fluid.

In some embodiments, the method includes supplying the therapeutic fluidthrough a port between the expandable portions. In some embodiments, thetherapeutic fluid is gaseous therapeutic fluid.

According to an aspect of some embodiments of the present inventionthere is provided a method for treating a bladder using a catheter forultrasonic-driven bladder therapeutic agent delivery including:inserting a distal expandable portion of the catheter into the bladdervia a urethra, supplying fluid into the bladder through at least onefluid port in the catheter, emitting ultrasound energy and formingcavitations in the gassed fluid, draining the bladder content, andsupplying therapeutic fluid into the bladder through at least onetherapeutic fluid port in the catheter. In some embodiments, said fluidis gassed.

In some embodiments, the method includes expanding a distal expandableportion of the catheter prior to supplying therapeutic fluid into thebladder. In some embodiments, the method includes draining and flushingthe bladder with saline prior to supplying the gassed fluid into thebladder.

In some embodiments, the method includes stopping emitting ultrasoundenergy during the draining of the bladder content and/or the supplyingof the therapeutic fluid into the bladder through at least onetherapeutic fluid port in the catheter. In some embodiments, the methodincludes further advancing a proximal expandable portion prior toemitting ultrasound energy. In some embodiments, the method includesexpanding proximal expandable portion prior to emitting ultrasoundenergy.

BRIEF DESCRIPTION OF THE FIGURES

Exemplary embodiments are illustrated in referenced figures. Dimensionsof components and features shown in the figures are generally chosen forconvenience and clarity of presentation and are not necessarily shown toscale. The figures are listed below.

FIGS. 1A and 1B, collectively referred to as FIG. 1, are a plan view andperspective enlarged view of the encircled area of FIG. 1A, simplifiedillustrations of a catheter for ultrasonic-driven bladder therapeuticagent delivery in accordance with some embodiments of the invention;

FIG. 2 is a perspective view simplified illustration of a catheter forultrasonic-driven bladder therapeutic agent delivery in accordance withsome embodiments of the invention;

FIG. 3 is a perspective view simplified illustration of a catheter forultrasonic-driven bladder therapeutic agent delivery in accordance withsome embodiments of the invention;

FIGS. 4A-4D are plan view simplified illustrations of a method ofimplementation of a catheter for ultrasonic-driven treatment of abladder, in accordance with some embodiments of the invention;

FIG. 5 a flow chart of a method for deploying of a catheter forultrasonic-driven treatment of a bladder wall, in accordance to someembodiments of the invention;

FIGS. 6A-6E are plan view simplified illustrations of a method ofimplementation of a catheter for ultrasonic-driven treatment of abladder, in accordance with some embodiments of the invention;

FIG. 7 is a flow chart of a method for deploying of a catheter forultrasonic-driven treatment of a bladder wall, in accordance to someembodiments of the invention;

FIGS. 8A and 8B, collectively referred to as FIG. 8, are a plan view anda perspective enlarged view of encircled area in FIG. 8A, simplifiedillustration of a catheter for ultrasonic-driven bladder therapeuticagent delivery in accordance with some embodiments of the invention;

FIG. 9 is a side view simplified illustration of a catheter forultrasonic-driven bladder therapeutic agent delivery in accordance withsome embodiments of the invention;

FIG. 10 is a side view simplified illustration of a catheter forultrasonic-driven bladder therapeutic agent delivery in accordance withsome embodiments of the invention;

FIG. 11 is a side view simplified illustration of a catheter forultrasonic-driven bladder therapeutic agent delivery in accordance withsome embodiments of the invention;

FIG. 12 is a side view simplified illustration of a catheter forultrasonic-driven bladder therapeutic agent delivery in accordance withsome embodiments of the invention;

FIG. 13 is a side view simplified illustration of a catheter forultrasonic-driven bladder therapeutic agent delivery in accordance withsome embodiments of the invention;

FIG. 14 is a side view simplified illustration of a catheter forultrasonic-driven bladder therapeutic agent delivery in accordance withsome embodiments of the invention;

FIG. 15 is an exemplary chart of parameters of implementation of acatheter for ultrasonic-driven treatment of a bladder, in accordancewith some embodiments of the invention;

FIG. 16 is a graph of the contractility of the detrusor muscle aftereach treatment: treatments using catheter for ultrasonic-driventreatment of a bladder compared to untreated tissue, and gold standard100 units Botox® intravesical injections; and

FIG. 17, which is a table of efficacy data from two human patientscomparing pre-procedure bladder function to 14 days post procedurebladder function.

DETAILED DESCRIPTION

Some of the challenges that exist in the ultrasound cavitation mechanismare in that cavitation may need to form in a fluid in proximity to thetissue surface to be treated to enhance therapeutic agent delivery.Moreover, the cavitation bubbles need to be prevented from forming nearor on the ultrasonic transducer surface, thereby blocking the ultrasonicwaves.

According to an aspect of some embodiments of the present inventionthere is provided a catheter for ultrasonic-driven bladder therapeuticagent delivery. In some embodiments, the catheter comprises a tube, oneor more transducers mounted on the tube, at least one expandableportion, and a transducer sleeve. In some embodiments, the transducersleeve is configured to enclose one or more transducers, wherein avolume is defined between the enclosed transducer and walls of thetransducer sleeve. In some embodiments, the transducer sleeve isdisposed between at least two expandable portions. In some embodiments,the transducer sleeve interconnects at least two expandable portions.

According to some embodiments of the invention, the tube comprises atleast one fluid port configured to supply fluid to or remove fluid fromat least one of the at least one expandable portion. In someembodiments, the expandable portion is inflated by fluid supplied intothe portions via the fluid ports. In some embodiments the transducersleeve is expandable.

According to some embodiments of the invention, the tube comprises atleast one therapeutic fluid port configured to supply therapeutic fluidinto the bladder. In some embodiments, the tube comprises at least onetherapeutic fluid port at a distal end of the tube. In some embodiments,the tube comprises at least one therapeutic fluid port between thetransducer sleeve and either one of the expandable portions. In someembodiments, the tube comprises at least one therapeutic fluid portbetween the transducer sleeve and a proximal expandable portion. As usedherein, the term “Proximal” means close to the operator and away fromthe subject being treated and the term “Distal” means distant from theoperator and towards the subject being treated. In some embodiments,fluid can be removed via the therapeutic fluid port.

In some embodiments the at least one expandable portion at an expandedstate is shaped as a sphere or a spheroid. In some embodiments, the atleast one expandable portion at an expanded state is toroidal. In someembodiments, the at least one expandable portion at an expanded statecomprises a C-shaped cross-section. In some embodiments, the at leastone expandable portion at an expanded state comprises an umbrellaconfiguration. In some embodiments, the catheter comprises a expandableportion shaped at an expanded state as a “dog-bone” having two expandedportions interconnected by a transducer sleeve.

In some embodiments, the at least one expandable portion is configuredto maintain at least a portion of the internal bladder surface distantfrom the transducer sleeve. In some embodiments, the transducer sleevedefines a lumen and the catheter transverses via the lumen. In someembodiments, one or more transducers are mounted on a portion ofcatheter inside the transducer sleeve lumen. In some embodiments, thetransducer is surrounded by a fluid that occupies a volume definedbetween the transducer and the transducer sleeve surrounding thetransducer. In some embodiments of the invention, the fluid cools theenclosed transducers. In some embodiments the fluid is an acoustic fluidfor an efficient delivery of acoustic waves produced by a transducer.

According to some embodiments, the transducer sleeve at an expandedstate is cylindrical. In some embodiments, the maximal cross-sectionalarea of the transducer sleeve at an expanded state is smaller than themaximal cross-sectional area of any one of the expandable portions at anexpanded state at any point along their longitudinal axis. In someembodiments, the maximal cross-sectional area of the transducer sleeveat an expanded state is two thirds of a maximal cross-sectional area ofthe expandable portions at an expanded state at any point along theirlongitudinal axis. In some embodiments, the maximal cross-sectional areaof the transducer sleeve at an expanded state is one third of themaximal cross-sectional area of the expandable portions at an expandedstate at any point along their longitudinal axis. According to someembodiments, the tube, at least one of the expandable portions, and thetransducer sleeve are concentric.

According to some embodiments of the invention, the expandable portionsare configured to occupy a portion of the bladder volume at an inflatedstate, while defining a treatment volume defined by the transducersleeve wall, walls of the expanded portions disposed at each end of thetransducer sleeve and the bladder wall. In some embodiments, theexpandable portions occupy at least one half of the bladder volume at aninflated state. In some embodiments, the expandable portions occupybetween one third and two thirds of the bladder volume when bladder isat an inflated state. This configuration directs a therapeutic agentcontaining fluid within the bladder into the treatment volume in thevicinity of the transducer, while protecting sensitive regions of thebladder e.g., the vesical trigone, at the internal surface of thebladder from being treated by the therapeutic agent and/or beingaffected by energy transmitted by the transducer. In some embodiments ofthe invention, at least some of the expandable portions are configuredto apply pressure on internal surfaces of the bladder at an expandedstate.

According to some embodiments of the invention, at least one of theexpandable portions is configured to engage the bladder wall at anexpanded state and block drainage of fluid from the treatment volume tobetween the expandable portions and the bladder wall. In someembodiment, an expandable portion at an expanded state maintains thetube concentric with the bladder wall.

According to some embodiments of the invention, the expandable portionsand the transducer sleeve are portions of the same balloon mounted onthe tube. In some embodiments, the transducer sleeve is inelastic havingfixed expanded dimensions. In some embodiments, the transducer sleeve isrigid or comprises a stiffening element.

According to some embodiments of the invention, the catheter comprises agap between the transducer and the tube. In some embodiments, the gap isin the range of 0.05 mm to 4 mm. According to some embodiments, the gapis in the range of 0.1 mm to 2.5 mm. In some embodiments the transduceris connected to the tube via spacers.

According to an aspect of some embodiments of the present inventionthere is provided a catheter for ultrasonic-driven bladder therapeuticagent delivery. The catheter comprises a tube, a proximal expandableportion, one or more transducers mounted on the tube between theproximal expandable portion and a distal end of the tube and atransducer sleeve enclosing one or more of the transducers. In someembodiments, the transducer sleeve has deflated state and an expandedstate.

In some embodiments, the proximal expandable portion and the transducersleeve comprise distinct balloons. In some embodiments, the proximalexpandable portion and the transducer sleeve comprise portions of oneballoon. In some embodiments the proximal expandable portion at anexpanded state is shaped as a sphere or spheroid. In some embodimentsthe proximal expandable portion at an expanded state is shaped as atoroid. In some embodiments, at least one of the proximal expandableportions at an expanded state comprises a C-shaped cross-section. Insome embodiments, at least the proximal expandable portions at anexpanded state comprises an umbrella configuration.

According to some embodiment of the invention, the tube comprises atleast one therapeutic fluid port configured to supply therapeutic fluidinto the bladder. In some embodiments, the therapeutic fluid port islocated between the transducer sleeve and the proximal expandableportion. In some embodiments, fluid can be removed via the therapeuticfluid port.

According to some embodiments, the proximal expandable portion comprisesa balloon that at an expanded state holds the tube at a pre-definedposition within the bladder. In some embodiments the proximal expandableportion is configured to engage the bladder wall at an expanded stateand block a drainage of fluid from a treatment volume within the bladderto between the proximal expandable portion wall and the bladder wall.

According to some embodiments of the invention, the transducer sleeve atan expanded state is cylindrical having a uniform cross section at leastat a portion of its length. In some embodiments, the maximalcross-sectional area of the transducer sleeve at an expanded state issmaller than the maximal cross-sectional area of the proximal expandableportion at an expanded state at any point along their longitudinal axis.In some embodiments, the maximal cross-sectional area of the transducersleeve at an expanded state is two thirds of a maximal cross-sectionalarea of the proximal expandable portion at an expanded state at anypoint along their longitudinal axis. In some embodiments, the maximalcross-sectional area of the transducer sleeve at an expanded state isless than 50% the maximal cross-sectional area of the proximalexpandable portion at an expanded state at any point along theirlongitudinal axis. According to some embodiments, the tube, the proximalexpandable portion, and the transducer sleeve are concentric.

According to some embodiments of the invention, the transducer sleeve atan expanded state does not intersect with an imaginary cone extendingbetween an apex located at the distal end of the tube, and a planedefined by the circumference of the expandable portion at an expandedstate. According to some embodiment of the invention, the transducersleeve is inelastic having limited expanded dimensions. In someembodiments, the transducer sleeve is rigid or comprises a stiffeningelement.

In some embodiments, the therapeutic agent fluid may be a non-gassedfluid. However, in some embodiments, the amount of cavitation bubblesgenerated in the therapeutic agent fluid are increased by providing agassed therapeutic agent fluid. Therefore, according to an aspect ofsome embodiments of the present invention there is provided a method forincreasing the amount of cavitation bubbles within a therapeutic agentused with a catheter for ultrasonic-driven bladder therapeutic agentdelivery. In some embodiments, the method comprises pressurizing asterile liquid with a gas and generating a “gassed liquid”. In someembodiments, the method comprises releasing a therapeutic agent into thegassed liquid and forming a gassed therapeutic fluid. In someembodiments, the method comprises inserting the gassed therapeutic fluidinto the bladder via a catheter for ultrasonic-driven bladdertherapeutic agent delivery and forming cavitation in the therapeuticfluid. According to some embodiments of the invention, the methodcomprises, for example pressurizing a sterile liquid with a gascomprises pressurizing at a pressure of about 8 to 30 atmospheres andfor a predetermined duration.

In some embodiments, the therapeutic agent fluid is mixed with anon-gassed fluid instead of a gassed fluid.

In some embodiments, the catheter comprises an expandable portion suchas a balloon, a stent, or any combination thereof. In some embodiments,at least one expandable portion comprises a stent.

Reference is now made to FIGS. 1A and 1B, collectively referred to asFIG. 1, which is a side view with a perspective enlarged view,simplified illustration of a catheter for ultrasonic-driven bladdertherapeutic agent delivery in accordance with some embodiments of theinvention. As shown in FIG. 1, a catheter 10 comprises a tube 11, atransducer 30 mounted on tube 11 and an expandable portion 20 mounted ontube 11 and enclosing transducer 30. In the exemplary embodimentdepicted in FIG. 1, the expandable portion 20 is a balloon. In someembodiments, expandable portion 20 comprises two expandable portions 24and 26 coupled to and sandwiching a transducer sleeve 22 disposed inbetween. The tube 11 comprises at least one fluid ports 14 and 15,configured to supply or to remove fluid out of at least one of theballoon 20 portions 22, 24 and 26. The transducer sleeve 22 encapsulatesthe transducer 30 and defines a volume between the walls of thetransducer sleeve 22 and the transducer.

In some embodiments, the tube comprises one or more conduits, or inother words, fluid supply channels, (not shown) supplying fluid from afluid source to one or more ports. The terms “conduits” and “fluidsupply channels” as used herein are interchangeable. The one or morefluid supply channels are disposed inside the tube or along an outersurface of the tube. In some embodiments, a fluid flow is generatedwithin the balloon 20 and at least within the internal volume of thetransducer sleeve 22 by providing fluid via one of the fluid ports, e.g.port 14, and removing fluid via another fluid port, e.g. port 15.

In some embodiments, the fluid provided into the balloon comprises anacoustic fluid. The term “acoustic fluid”, as referred to herein,relates to a fluid with high cavitation energy threshold to preventformation of cavitation bubbles in this liquid during operation of theultrasound that would interfere with acoustic waves, and prevent damageto the catheter. The acoustic fluid allows efficient progression ofultrasound energy. An aspect of this fluid is that it reducescavitation, which may block ultrasound energy from progressing from thetransducer to the bladder internal surface. Such fluid may be a degassedfluid, e.g. a degassed solution such as saline which went throughboiling, or a solution which its gas content was filtered out. Theacoustic fluid assists in transmitting the acoustic waves produced bythe transducer 30 through the surface of the transducer sleeve 22 to thetherapeutic fluid surrounding the transducer sleeve. The acoustic fluidcan also cool the enclosed transducers 30, for example by heatconvection. By the cooling of the transducers, the transducers can beoperated in desired parameters for a longer treatment duration. Inaddition, the overheating of the bladder tissues by heated transducersis avoided.

The acoustic fluid provided into the transducer sleeve 22 does notcontain gas bubbles to serve as nucleation seeds for the generation ofcavitation and therefore distances the cavitation phenomenon from thetransducer 30 and towards the bladder wall. The ultrasound waves travelfrom the transducer through the acoustic fluid without generatingcavitation, hence are free to travel through this medium towards thesurface of the sleeve 22. Then, the waves travel through the therapeuticfluid located in a therapeutic volume between the sleeve and the bladdertowards the bladder tissue. In the therapeutic fluid cavitation isgenerated, thereby, resulting in the delivery of the therapeutic agentinto the bladder. This allows the transducer to be disposed farther fromthe bladder internal surface than transducers exposed to therapeuticfluid inside the bladder. Production of cavitation increases theefficacy of the ultrasound treatment as described in detail in U.S.patent application Ser. No. 15/561,733 to the same inventors.

As shown in the exemplary embodiment depicted in FIG. 1 and View A ofFIG. 1, the tube 11 comprises a tip 16 which comprises a plurality offluid port(s) 17. In some embodiments, tip 16 is convex and configuredto allow easier insertion of the catheter into the bladder and reduceaccidental damage to the interior surface of the bladder during thedeployment of the catheter within the bladder. In some embodiments, tip16 has oblong geometry having fluid ports at a distal end of the tip. Insome embodiments, tip 16 has no ports. The bladder fluid ports 17 can beused, for example, for one or more of the following functions: insertingtherapeutic fluid into the bladder, removing therapeutic fluid out ofthe bladder, inserting tissue cleaning fluid, such as saline to remove atherapeutic fluid, and removing fluid out of the bladder, e.g. urinefilling a urine bladder prior to treatment. In some embodiments, theshape of tip 16 is one of a toroid, torus, disk, sphere, andsemi-sphere. In some embodiments, the tip 16 is rigid or semi-rigid. Insome embodiments, the port(s) 17 are distributed along at least aportion of the circumference of the tip 16. In some embodiments, the tip16 comprises a surface 40 positioned distally in relation to the port(s)17. In some embodiments, the surface 40 is rounded. In some embodiments,the tip 16 is blind. In some embodiments, fluid flowing within tube 11exits port(s) 17.

A potential advantage of a plurality of openings (ports) is in thatmultiple ports provide a redundancy in cases of clogged ports wheninserting or removing fluid. In some embodiments in which the transducersleeve and an expandable portion are disposed on distinct balloons, atleast one therapeutic fluid port can be disposed at the tube, betweenthe transducer sleeve and the expandable portion. In some embodiments,at least one therapeutic fluid port can be disposed at the tube at aproximal tube portion which is not covered by any expandable portion.

In some embodiments, the fluid port(s) 17 are positioned radially aroundthe longitudinal axis of the catheter and/or tube. In some embodiments,the fluid port(s) 17 are positioned such that a fluid streaming from thefluid port(s) 17 is ejected at a nonzero angle in relation to thelongitudinal axis of the catheter and/or tube.

For example, in the exemplary embodiment depicted in FIG. 1 and View Aof FIG. 1, when the catheter 10 is inserted into a bladder such that tip16 is urged against the wall of the bladder (e.g., the surface oppositethe trigone) marked region 5″, or other portions of the urinary bladderwall, the bladder wall does not obstruct the fluid port(s) 17.

In some embodiments, the tip 16 comprises a distal opening of the distalportion 11 b of tube 11. In some embodiments, the tip 16 comprises atleast one port 17 at the surface 40. In some embodiments, the tip 16comprises a cover comprising at least one aperture, such as a mesh. Insome embodiments, the tip 16 cover is rigid or semi rigid. In someembodiments, the cover defines a volume around the tip 16.

For example, in some embodiments, when the catheter 10 is inserted intoa bladder such that the cover of tip 16 is urged against the wall of thebladder, for example, the distal portion of the bladder (such as thesurface opposite the trigone) marked region 5″, or other portions of theurinary bladder wall, the bladder wall does not obstruct at least oneaperture of the tip 16 cover.

In some embodiments, at least one of the transducer, at least one of theexpandable portion, and the tube are concentric. In some embodiments, atleast two expandable portions are concentric. In some embodiments, thetransducer and at least one expandable portion are concentric. In someembodiments, the transducer sleeve and at least one expandable portionare concentric. In some embodiments, the transducer sleeve and thetransducer are concentric.

An advantage of the concentric positions of the catheter, expandableportion, transducer sleeve and/or transducer is in that the cathetermaintains equal distance between the internal bladder wall and thetransducer, such that the treated portion of the bladder wall mayreceive equal or nearly-equal treatments. Additionally, in someembodiments, the treated portion of the bladder wall may receivepredetermined varying treatment.

In some embodiments, the tube 11 comprises one or more conduits whichsupply fluid to one or more of the ports 14/15/17. In some embodiments,each conduit opens to a specific port 14/15/17. In some embodiments,each conduit opens to a separate port 14/15/17. In some embodiments, aconduit opens to at least one of the ports 14/15/17.

In some embodiments, tube lumen 11 comprises at least one conduit. Insome embodiments, at least one conduit is in fluid communication with aproximal opening 34/36/38 of the catheter 10.

In some embodiments, the catheter 10 comprises at least one proximalopening 34/36/18 through which fluid passes into and/or out of one ormore ports 14/15/17. In some embodiments, a proximal opening 34/36/38 isin fluid communication with a reservoir for fluid, such as, for example,a therapeutic fluid, a fluid (e.g. saline), a gassed fluid, and anacoustic fluid. In some embodiments, a proximal opening 34/36/38 is influid communication with a drainage bag. In some embodiments, at leastone conduit is coupled to one or more of the proximal openings 34/36/38.In some embodiments, each of the proximal openings 34/36/38 is in fluidcommunication with at least one of the ports 14/15/17.

FIG. 2 is a perspective view simplified illustration of implementationof an ultrasonic-driven bladder therapeutic agent delivery inside abladder 1 in accordance with some embodiments of the invention. In theexemplary embodiment depicted in FIG. 2, expandable portions 24 and 26are spheroid in geometry and in an expanded state. In some embodiments,both expandable spheroid portions 24 and 26 occupy a portion of thebladder volume, thereby forming a treatment volume 7 surrounding thetransducer sleeve 22 between the expandable spheroid portions 24 and 26and the bladder wall 5. A potential advantage of this configuration isin that a therapeutic agent disposed within the bladder 1 will bedirected into the treatment volume 7 between the transducer 30 and thebladder wall 5, limiting the treatment on bladder tissues to section 5′of the bladder wall and the treatment volume 7 and benefiting from thefull effect of cavitation formed by transducer 30. Additionally, in someembodiments, this configuration directs a therapeutic agent containingfluid within the bladder 1 into the treatment volume 7, while protectingregions e.g., the vesical trigone, at the internal surface of thebladder 1 from being treated by the therapeutic agent and/or energytransmitted by the transducer 30. In some embodiments, the expandableportions 24 and 26 occupy between 30% and 70% of the bladder volume atan expanded state. In some embodiments, the expandable portions 24 and26 occupy between 40% and 60% of the bladder volume at an expandedstate.

Normally, in a relaxed state, a bladder wall is undulated in shape. Insome embodiments, the inflated balloon 20 applies tension in theinternal surface 5 of the bladder 1 in a plurality of directions,thereby straightening at least a portion of the bladder wall of thebladder at least in region 5′ bordering the treatment volume 7 betweenexpandable portion 24 and 26 as shown in FIG. 2.

Since the expanded balloon has a predictable geometry and dimensions ata pre-defined pressure, the measurements of the treatment volume 7surrounding the transducer 30 are also predictable. Expandable portions24 and 26 can be designed to have a circumference at a fully expandedstate that will define a pre-determined distance L1 between thetransducer 30 and the bladder treated surface 5′. In some embodiments, auniform treatment is achieved by having the treated tissues atequidistance from the transducer. In some embodiments, the concentrationof the therapeutic agent within the therapeutic fluid are determined bythe predictable treatment volume 7. Straightening and stretching thebladders' tissues contribute to the efficacy of the treatment byincreasing the permeability of the therapeutic agent into the bladdertissues. In addition, such structural configuration stabilizes thebladder wall and increases the safety of the procedure by preventing thecollapse of the bladder wall onto or close to the hot transducersurface. In addition, the transducer sleeve 22 prevent a direct contactbetween the bladder and the transducer 30.

In some embodiments, and as described in greater detail elsewhereherein, one or more of the expandable portions is a stent.

In some embodiments, e.g., in treatment of the urinary bladder, theprocedure is carried out when the bladder is positioned vertically orclose to vertically wherein the trigone is lowest portion of the urinarybladder. In some embodiments, as shown in FIG. 2, the distal expandableportion 26 does not seal a distal portion of the bladder (e.g., thesurface opposite the trigone) marked region 5″. The therapeutic fluidprovided through ports 17 can then flow into the volume 7, e.g. bygravity or by pressure gradient. In some embodiments, the proximalexpandable portion 24, as illustrated in FIG. 2, engages the proximalsurface of the bladder. At an expanded state, the expandable portion 24can block a drainage of fluid from the therapeutic volume 7 beingpressed against the bladder wall. The expandable portion 24 can bepressed against and seal the proximal surface of the bladder (e.g. bystatic forces, such as gravity, fluid pressure, distal spheroid pressingagainst a distal bladder surface). Thereby, the therapeutic fluidremains within the therapeutic volume 7 during the treatment, whilebladder tissues located beyond the expandable portion 24 are protectedfrom being exposed and treated by the therapeutic fluid and the acousticenergy.

In some embodiments, the proximal and/or distal expandable portion 24/26shields portions of the bladder wall from ultrasonic energy. In someembodiments, the proximal expandable portion 24 shields the trigone fromultrasonic energy. In some embodiments, the proximal and/or distalexpandable portion 24/26 acts as a vessel for a cooling fluid flow whichincreases heat dissipation from the transducer.

In some embodiments, at least one of the proximal and/or distalexpandable portion 24/26 is filled with fluid which has high acousticimpedance and therefore is non-conducive to ultrasound energy. In someembodiments, the non-conducive fluid inflates at least one of theproximal and/or distal expandable portion 24/26. In some embodiments,the non-conducive fluid prevents transmission of ultrasound energy tothe untreated areas of the bladder (e.g., the trigone).

A potential advantage of having the non-conducive fluid within one ormore expandable portions 24/26 is in that ultrasound energy is nottransmitted to portions of the bladder which are not treated.

In some embodiment of the invention, expandable portion 24 serves as acatheter support and fixes the position of the tube 11 within thebladder 1. In some embodiments, fluid within one or more expandedportions engaging an internal surface 5 of the bladder 1, cools thebladder by heat transfer between the bladder wall and the fluid.

In some embodiments, the volume and/or shape of the expandable portions24/26 determine the distance between the bladder treated surface 5′ andthe transducer 30. In some embodiments, the volume and/or shape of theexpandable portions 24/26 determine the distance between the bladdertreated surface 5′ and the transducer sleeve 22. In some embodiments,the distance between the bladder treated surface 5′ and the transducer30 and/or the transducer sleeve 22 is predetermined.

The temperature of the bladder treated surface 5′ is correlated with theheat given off by the transducer. Therefore, increasing the distancebetween the transducer 30 and the bladder treated surface 5′ preventsover-heating of the bladder treated surface 5′. In some embodiments,increasing the distance between the transducer 30 and the bladdertreated surface 5′ permits heating of the transducer 30 to highertemperatures, for example, by increasing on-time and/or frequencyemitted by the transducer.

In some embodiments, increasing the frequency emitted by the transducerincreases the efficacy of the treatment by increasing the cavitationwithin the therapeutic fluid (and/or combination of the gassed fluid andtherapeutic fluid). In some embodiments, increasing the on-time of thetransducer increases the efficacy of the treatment by increasing thecavitation within the therapeutic fluid (and/or combination of thegassed fluid and therapeutic fluid).

As shown in FIG. 3, according to some embodiment of the invention,expandable portions 24 and 26 define a cylinder 23 therebetween, thewall of the cylinder outlined by broken lines, congruent with thelargest circumference of the expandable portions 24/26 at Y1 and Y2respectively. In some embodiments and as explained in detail elsewhereherein, the maximal cross-sectional area of the transducer sleeve 22taken at Y3 is smaller than the maximal cross-sectional area of theexpanded portions 24 and 26. In some embodiments a diameter D10 ofexpandable portions 24 and 26 is between 20 mm and 40 mm at an expandedstate. In some embodiments, a diameter D10 of expandable portions 24 and26 is between 20 and 40 mm at an expanded state. In some embodiments, adiameter D20 of a transducer sleeve 22 is between 5 mm and 15 mm. Insome embodiments, a diameter D20 of a transducer sleeve 22 is between 6mm and 12 mm. In some embodiments, a diameter D20 of a transducer sleeve22 is between 8 mm and 10 mm. In some embodiments a length L30 of thetransducer sleeve is between 5 and 25 mm at an expanded state. In someembodiments a length L30 of the transducer sleeve is between 10 and 15mm at an expanded state.

In some embodiments, the transducer sleeve at an expanded state iscylindrical having a uniform cross section at least at a portion of itslength. In some embodiments, the maximal cross-sectional area of thetransducer sleeve at an expanded state is smaller than the maximalcross-sectional area of the proximal expandable portion at an expandedstate at any point along their longitudinal axis. In some embodiments,the maximal cross-sectional area of the transducer sleeve at an expandedstate is two thirds of a maximal cross-sectional area of the proximalexpandable portion at an expanded state at any point along theirlongitudinal axis. In some embodiments, the maximal cross-sectional areaof the transducer sleeve at an expanded state is less than 50% themaximal cross-sectional area of the proximal expandable portion at anexpanded state at any point along their longitudinal axis. According tosome embodiments, the tube, the proximal expandable portion, and thetransducer sleeve are concentric.

In some embodiments, the length of the transducer 30 is 3-20 mm. In someembodiments, the length of the transducer 30 is 4-14 mm. In someembodiments, the length of the transducer 30 is 5-10 mm. In someembodiments, the length of the transducer 30 is 6 mm.

In some embodiments, the width of the transducer 30 is 3-14 mm. In someembodiments, the width of the transducer 30 is 3-7 mm. In someembodiments, the width of the transducer 30 is 3-5 mm. In someembodiments, the width of the transducer is 4 mm.

In some embodiments, the thickness of the transducer 30 is 10-40 mm. Insome embodiments, the thickness of the transducer 30 is 15-30 mm. Insome embodiments, the thickness of the transducer 30 is 15-23 mm. Insome embodiments, the thickness of the transducer 30 is 20 mm.

In some embodiments, the balloon wall comprises regions having variableelasticity so that, for example, only portions of the balloon wall areelastically expandable. E.g. diametrically opposed faces 24 a and 24 c(FIG. 1) of expandable portion 24 can be produced as an inelastic face,while a face 24 b along the circumference of expandable portion 24 iselastically flexible, hence the expansion of portion 24 will be greaterradially expansion along catheter tube 11.

In some embodiments at least one of the expandable portions at anexpanded state is shaped as at least one of a sphere, a spheroid and atoroid. In some embodiments, at least one of the expandable portions atan expanded state comprises a C-shaped cross-section. In someembodiments, at least one of the expandable portions at an expandedstate comprises an umbrella configuration.

In some embodiments, the transducer sleeve at an expanded state iscylindrical. In some embodiments, the maximal cross-sectional area ofthe transducer sleeve at an expanded state is smaller than the maximalcross-sectional area of any one of the expandable portions at anexpanded state at any point along their longitudinal axis. In someembodiments, the maximal cross-sectional area of the transducer sleeveat an expanded state is two thirds of a maximal cross-sectional area ofthe expandable portions at an expanded state at any point along theirlongitudinal axis. In some embodiments, the maximal cross-sectional areaof the transducer sleeve at an expanded state is one third of themaximal cross-sectional area of the expandable portions at an expandedstate at any point along their longitudinal axis. In some embodiments,the tube, at least one of the expandable portions, and the transducersleeve are concentric.

In some embodiments of the invention, the expandable portions areconfigured to occupy a portion of the bladder volume at an inflatedstate, while defining a treatment volume defined by the transducersleeve wall, walls of the expanded portions disposed at each end of thetransducer sleeve and the bladder wall. In some embodiments, theexpandable portions occupy at least one half of the bladder volume at aninflated state. In some embodiments, the expandable portions occupybetween one third and two thirds of the bladder volume when bladder isat an inflated state. This configuration directs a therapeutic agentcontaining fluid within the bladder into the treatment volume in thevicinity of the transducer, while protecting sensitive regions of thebladder e.g., the vesical trigone, at the internal surface of thebladder from being treated by the therapeutic agent and/or beingaffected by energy transmitted by the transducer. In some embodiments ofthe invention, at least some of the expandable portions are configuredto apply pressure on internal surfaces of the bladder at an expandedstate.

In some embodiments, shaping of any of the balloons can done by:molding, differential thickness, varying materials, integral elements,etc. Another method for shaping any of the balloon portions can be bylimiting its expansion by external elements, such as a sleeve or a net.

In some embodiments, the tube 11 has a uniform cross section throughoutits length. In some embodiments, a distal portion 11 b of tube 11comprises a smaller diameter than the diameter of proximal portion 11 aof tube 11. In some embodiments, as shown in view A in FIG. 1, portion11 b comprises the distal tip 16. In some embodiments, portion 11 b isconnected to tube 11 under a proximal edge of transducer 30. In someembodiments, transducer 30 is mounted on portion 11 b of tube 11 so thatan external surface of transducer 30 is positioned flush with proximalportion 11 a of tube 11. In some embodiments portion 11 b comprises anarrow tube portion inserted within tube 11.

In some embodiments, each of ports 14/15 are supplied by distinct fluidsupply channel so that supplying fluid to expandable portion 26 via port15 does not necessarily expand expandable portion 24 and vice versa,even though expandable portions 24/26 are in fluid communication viatransducer sleeve 22. In some embodiments port 15 is associated with adistinct fluid supply channel of the tube 11. In some embodiments, port14 is configured to be closed when providing fluid by port 15. Apotential advantage in the configuration of ports 14/15 is in thatduring deployment, expandable portion 26 is configured to be inflatedwhile expandable portion 24 is still within urethra 3, i.e., withoutexpanding expandable portion within urethra 3, which may be painful tothe subject being treated.

Reference is now made to FIGS. 4A to 4D, which are plan view simplifiedillustrations of the method of implementation of a catheter forultrasonic-driven treatment of a bladder. As shown in FIGS. 4a to 4d ,the catheter for ultrasonic-driven treatment of a bladder is deployedby:

-   -   Inserting (as shown in FIG. 4A) a catheter 10 into bladder 1        through a urethra 3;    -   Expanding (FIG. 4B) balloon 20, including expandable portions        24, 26 and transducer sleeve 22, to a pre-determine pressure or        volume by a pressurized acoustic fluid (e.g. 20 cc-40 cc of        fluid) and keeping expanded portions 24/26 and transducer sleeve        22 at an expanded state;    -   Draining the bladder 1 of fluid through therapeutic fluid        port(s) 17;    -   Supplying saline through therapeutic fluid port(s) 17;    -   Mixing therapeutic fluid with gassed liquid as described        elsewhere herein (this step can be performed any time prior or        during the deployment of the catheter); and    -   Supplying (FIG. 4C) a therapeutic fluid (e.g. 20-40 cc) into the        bladder via therapeutic fluid port(s) 17. In some embodiments,        such as depicted by arrow 400, therapeutic fluid is supplied via        therapeutic fluid port(s) 17 into the bladder lumen.

Reference is now made to FIG. 5, which is a flow chart of a method fordeploying of a catheter for ultrasonic-driven treatment of a bladderwall in accordance to some embodiments of the invention and tocorresponding FIGS. 6A to 6E, which are side-view simplifiedillustrations of the method of implementation of a catheter forultrasonic-driven treatment of a bladder. As shown in FIG. 5, thecatheter 10 for ultrasonic-driven treatment of a bladder 1 is deployedby:

-   -   Inserting at step 1000 distal expandable portion 26 of catheter        10 into bladder 1 through urethra 3;    -   Removing at step 1010 urine from the bladder via port(s) 17;    -   Expanding at step 1020 portion 26 to an expanded state by        providing fluid into portion 26 via port 15;    -   Optionally, Mixing at step 1030 therapeutic fluid with gassed        liquid as described elsewhere herein (this step can be performed        any time prior or during the deployment of the catheter);    -   Supplying at step 1040 therapeutic fluid through the therapeutic        fluid port(s) 17;    -   Further advancing at step 1050 proximal expandable portion 24        into bladder 1 through urethra 3; and    -   Expanding at step 1060 proximal expandable portion 24 to an        expanded state by providing fluid via port 14.

In some embodiments, the method comprises expanding the proximalexpandable portion and trapping the therapeutic fluid between the distalexpandable portion and the proximal expandable portion.

A potential advantage in using the method for deployment of theultrasonic-driven catheter 10 is in that most of the therapeutic fluiddoes not remain trapped at a distal volume between the distal expandableportion 26 and the bladder wall 5″ opposite to the bladder trigone.

FIG. 6A is a plan view simplified illustration of the insertion ofdistal expandable portion 26 into bladder 1 through urethra 3. In someembodiments, the proximal expandable portion 24 remains within theurethra 3.

FIG. 6B is a plan view simplified illustration of the expanding ofdistal expandable portion 26 to an expanded state by providing fluidinto distal expandable portion 26 via fluid port 15 (for example, asdepicted by arrow 600). In some embodiments, the distal expandableportion 26 and the proximal expandable portion 24 are in fluidcommunication. The fluid remains in distal expandable portion 26, flowin the direction of proximal expandable portion 24 countered by externalpressure applied to proximal expandable portion 24 by the urethra wall.Accordingly, the proximal expandable portion 24 remains contractedwithin the urethra due to pressure applied to the proximal expandableportion 24 by the urethra walls. In some embodiments, the proximalexpandable portion 24 remains mostly contracted within the urethra.

FIG. 6C is a plan view simplified illustration of supplying oftherapeutic fluid through the therapeutic fluid port(s) 17. In someembodiments, the method comprises supplying therapeutic fluid throughthe therapeutic port(s) 17 into the volume 46 defined by the distalexpanding portion 26 and the bladder wall (for example, as depicted byarrow 602).

FIG. 6D is a plan view simplified illustration of the further advancingproximal portion 24 into bladder 1 through urethra 3. In someembodiments, during the further advancement of the proximal portion 24into bladder 1, proximal portion 24 is freed from external pressureapplied thereto by the urethra walls and at least a portion of the fluidinside the distal expandable portion 26 flows into the proximalexpandable portion 24 to equalize pressures within expandable portions24 and 26 in accordance with the law of LaPlace. In some embodiments,fluid inside the distal expandable portion 26 flows into the portion ofthe proximal expandable portion 24 which is within the bladder 1. Insome embodiments, the volume of the distal expandable portion 26decreases due to fluid flow into the proximal expandable portion 24. Insome embodiments, the decrease in volume of the distal expandableportion 26 increases flow of therapeutic fluid into the bladder volume48 surrounding the transducer sleeve 22. In some embodiments, thedecrease in volume of the distal expandable portion 26 creates orincreases a distance 50 between the distal expandable portion 26 and thebladder wall, which increases flow of therapeutic fluid to volume 48. Insome embodiments, the partially expanded proximal expandable portion 24provides a barrier for therapeutic fluid flowing into volume 48.

FIG. 6E is a plan view simplified illustration of the expanding ofportion 24 to an expanded state by providing fluid into portion 24 viafluid port 14 (for example, as depicted by arrow 604). In someembodiments, expanding proximal expandable portion 24 to an expandedstate by providing fluid via port 14 increases the volumes of both theproximal and distal expandable portions 24/26.

In some embodiments, the expandable portions 24/26 are separateballoons. In some embodiments, during or after the further advancementof the proximal portion 24 into bladder 1, at least a portion of thefluid inside the distal expandable portion 26 is removed via fluid port15. In some embodiments, the volume of the distal expandable portion 26decreases. In some embodiments, during or after the further advancementof the proximal portion 24 into bladder 1, the proximal expandableportion 26 is at least partially expanded by providing fluid via fluidport 14. In some embodiments, once therapeutic fluid enters the volume48 surrounding the transducer sleeve 22, the distal expandable portion26 is expanded by providing fluid into the distal expandable portion 26via fluid port 15.

In some embodiments, the ultrasonic-driven treatment performed bycatheter 10 inserted within a bladder 1 is carried out by a method inaccordance with some embodiments of the invention and includes:

-   -   Fixing catheter 10 within the bladder 1 by ensuring the expanded        balloon portion 24 engages the proximal surface 5 of the bladder        1;    -   Circulating at step 1070 the acoustic fluid within the        transducer portion 22 by providing acoustic fluid via a first        fluid port 15 and extracting acoustic fluid via a second fluid        port 14;    -   Activating at step 1080 the transducer 30; and    -   Forming at step 1090 cavitation in the therapeutic fluid inside        the bladder treatment volume.

In some embodiments, the ultrasonic-driven treatment performed bycatheter 10 inserted within a bladder 1 is terminated by the followingmethod, according to some embodiments of the invention:

-   -   Inactivating transducer 30;    -   Extracting therapeutic fluid through therapeutic fluid port(s)        17;    -   Supplying saline through therapeutic fluid port(s) 17 (e.g. to        clean the bladder); and    -   Collapsing the expanded portions 26, 22, 24 by releasing or        pumping the acoustic fluid out via one or more acoustic fluid        ports 14 and 15; and    -   Withdrawing catheter 10 out of the bladder 1 via urethra 3.

Reference is now made to FIG. 7, which is a flow chart of a method forthe deployment of a catheter for ultrasonic-driven treatment of abladder wall and the treatment of the bladder in accordance to someembodiments of the invention. As shown in FIG. 7, the method fordeployment of catheter 10 in bladder 1 is carried out as follows:

-   -   Inserting at step 1400 catheter 10 into bladder 1 through a        urethra 3;    -   Removing at step 1410 urine from the bladder 1 via port(s) 17;    -   Expanding at step 1420 expandable portions 24, 26 and transducer        sleeve 22, to a pre-determined pressure or volume by a        pressurized acoustic fluid (e.g. 20-40 cc of fluid) and keeping        expanded portions 24/26 and transducer sleeve 22 at an expanded        state; and    -   Optionally, draining at step 1430 the bladder of fluid through        therapeutic fluid port(s) 17.    -   In some embodiments of the invention and as further shown in        FIG. 7, deployment of the catheter is followed by a method of        treatment of the bladder comprising:    -   Supplying at step 1440 saline through therapeutic fluid port(s)        17;    -   Supplying at step 1450 an optionally gassed liquid as described        elsewhere herein through bladder therapeutic fluid port(s) 17;    -   Activating at step 1460 the transducer 30;    -   Inactivating at step 1470 transducer 30;    -   Draining at step 1480 the bladder of the optionally gassed fluid        through therapeutic fluid port(s) 17;    -   Supplying at step 1490 a therapeutic fluid (e.g. 20-40 cc)        through therapeutic fluid port(s) 17.

In some embodiments, the method comprises expanding the proximalexpandable portion and trapping the therapeutic fluid between the distalexpandable portion and the proximal expandable portion.

In summary and in accordance with some embodiments of the inventiontreatment of the bladder comprises at least the following methods:

Method A in which:

-   -   deploying a catheter for ultrasonic-driven treatment of a        bladder wall in a bladder;    -   supplying therapeutic fluid (e.g., Botox®) into the bladder;    -   forming cavitations in the fluid within the bladder; and    -   draining the bladder.

Method B in which:

-   -   deploying a catheter for ultrasonic-driven treatment of a        bladder wall in a bladder;    -   supplying therapeutic fluid (e.g., Botox®) into the bladder;    -   forming cavitations in the fluid within the bladder for a        predetermined period of time followed by    -   leaving the therapeutic fluid in the bladder for a predetermined        period of time; and    -   draining the bladder.

Method C in which:

deploying a catheter for ultrasonic-driven treatment of a bladder wallin a bladder;

-   -   supplying the bladder with gaseous fluid;    -   forming cavitations in the gaseous fluid;    -   draining the gaseous fluid; and    -   supplying the bladder with therapeutic fluid.

Method D in which:

-   -   deploying a catheter for ultrasonic-driven treatment of a        bladder wall in a bladder;    -   supplying the bladder with gaseous therapeutic fluid;    -   forming cavitation in the gaseous fluid for a predetermined        period of time;    -   followed by    -   draining the bladder.

Reference is now made to FIGS. 8A and 8B, collectively referred to asFIG. 8, which are a side view and perspective view simplifiedillustration of a catheter for ultrasonic-driven bladder therapeuticagent delivery in accordance with some embodiments of the invention. Asshown in FIG. 8, a catheter 110 comprises a tube 111, a proximal balloon124 mounted on the tube 111, and an expandable transducer sleeve 122.Turning to the enlarged view B in FIG. 8, in some embodiments, a distalportion 111 b of tube 111 comprises a smaller diameter than the diameterof proximal portion 111 a of tube 111. In some embodiments, as shown inview B in FIG. 8, portion 111 b comprises the distal tip 117. In someembodiments, portion 111 b is connected to tube 111 under a proximaledge of transducer 130. In some embodiments, transducer 130 is mountedon portion 111 b of tube 111 so that an external surface of transducer130 is positioned flush with proximal portion 111 a of tube 111. In someembodiments, portion 111 b comprises a narrow tube portion insertedwithin tube 111.

In some embodiments, a transducer 130 is mounted on tube 111 portion 111b between the proximal expandable portion 124 and a distal end 117 ofthe tube. In some embodiments, the transducer sleeve 122 accommodatesand encapsulates the transducer 130 and enables a flow of fluid at theinternal volume defined by the walls of transducer sleeve 122. In someembodiments, the tube 111 comprises one or more therapeutic fluidport(s) 116 at a proximal portion 111 a of the tube 111, which is freeof the expandable portions 122 and 124 and is exposed to the bladdervolume.

In some embodiments, proximal balloon 124 is expandable from a collapsedstate to an expanded state. In some embodiments, the expanded state isdefined as the maximal inelastic expansion of the balloon. In someembodiments, the expanded state of the balloon is defined as a maximalelastic expansion wherein the balloon is elastic. The tube 111 comprisesone or more fluid ports 114, 115 a and 115 b, configured to supply fluidto or remove fluid from at least one of the expandable portions 122 and124. Expandable portions 122 and 124 are expandable by supplying fluidunder positive pressure through at least one of the fluid ports 114, 115a and 115 b. In some embodiments, the tube 111 comprises one or morefluid supply channels (not shown), either inside the tube 111 and/oralong an outer surface of the tube. In some embodiments, a fluid flow isgenerated within a lumen defined by walls of transducer sleeve 122 byproviding fluid via one of the fluid ports, e.g. port 115 a, andremoving fluid via another fluid port, e.g. port 115 b. In someembodiments, fluid supply port, e.g. port 115 a and fluid removal port,e.g. port 115 b are disposed on diametrically opposed surfaces ofcatheter 110. In some embodiments, fluid supply port, e.g. port 115 a islocated on tube 111 portion 111 b whereas the fluid removal port, e.g.port 115 b is disposed on tube 111. In some embodiments, fluid supplyport, e.g. port 115 a and fluid removal port, e.g. port 115 b aredisposed on opposite sides of transducer 130. In some embodiments, fluidsupply port, e.g. port 115 a, and fluid removal port, e.g. port 115 b,are circumferentially rotated in respect to each other.

In some embodiments, the fluid inputted into the balloon comprises anacoustic fluid. The acoustic fluid maintains a fixed distance betweenthe surface of transducer 130 and transducer sleeve 122. In someembodiments, the acoustic fluid assists in cooling the enclosedtransducers 130, for example by heat convection.

In some embodiments, cooling of the transducers helps in their operatingin desired parameters for a longer treatment duration, thus, avoidingoverheating the tissues while providing an effective treatment. In someembodiments, and as described in greater detail elsewhere herein,removing heat from the transducers prevents overheating of the bladdertissue, which permits an increase in the range of the operationalparameters, such as, for example, longer treatment time and/or anincrease in transducer frequency.

In some embodiments, e.g., in treatment of the urinary bladder, theprocedure is carried out when the bladder is positioned vertically orclose to vertically wherein the trigone is lowest portion of the urinarybladder. As shown in the exemplary embodiment depicted in FIG. 9, whichis a side view simplified illustration of implementation of anultrasonic-driven bladder therapeutic agent delivery inside a bladder inaccordance with some embodiments of the invention, the proximal balloon124, at an expanded state, engages the proximal surface of the bladderat the trigone area. The proximal balloon 124 occupies a volume of thebladder 100, thereby forming a treatment volume 107. Balloon 124 at anexpanded state blocks drainage of fluid from volume 107 via the balloonwall which is urged against the bladder wall 105. In some embodiments,balloon 124 is urged against and seals the proximal surface (trigonearea) of the bladder 105′, for example by static forces, such as gravityor fluid pressure. Thereby, the therapeutic fluid remains within volume107 during the treatment, while the proximal surface (trigone area) ofthe bladder 105′ located distally to proximal balloon 124 remainsprotected from exposure to the therapeutic fluid and the acousticenergy. In some embodiment of the invention, balloon 124 serves as acatheter base and fixes the position and orientation of the tube 111 inrespect to the bladder as well as the elements mounted on the tubewithin the bladder 100.

When a treatment is not required on a distal region or other regions ofthe bladder, therapeutic fluid can be provided into the bladder in anamount which will fill only a portion of the bladder. During treatment,due to gravitation, the level of fluid will be lower than pre-determinedsurfaces, so will not be treated by the therapeutic fluid and acousticenergy. As shown in FIG. 10, which is a side view simplifiedillustration of implementation of an ultrasonic-driven bladdertherapeutic agent delivery inside a bladder in accordance with someembodiments of the invention, therapeutic fluid partially fills volume107 of the bladder 100. Since the bladder 100 is oriented vertically,the direction of gravitation indicated by an arrow (G), the therapeuticfluid remains in between levels E1 and E2. During the treatment, only aportion of the bladder wall which is located distally (above) toproximal balloon 124 in region 105″ and within volume 107 will receivethe therapeutic fluid and acoustic energy.

In some embodiments, the regions of the bladder wall affected by thetreatment are defined by the following dimensions of elements of thecatheter 100 such as, for example: the cross section of the proximalballoon 124, the distance between port 116 and face 124 b, and thedistance between port 116 and the transducer sleeve 122.

The transducer sleeve 122 isolates the transducer 130 from thetherapeutic agent and prevents cavitation bubbles from forming near oron the transducer surface. Thereby, the transducer can be disposedfarther from the bladder internal wall than in the absence of atransducer sleeve 122. This allows distribution of cavitation bubbleswithin treatment volume 107, to invoke cavitation on the bladder wall,thus increasing the efficacy of energy emitted towards the bladder wallby the transducers. Some parameters that determine the expandedgeometrical shape of the transducer sleeve 122 can be: size and numberof the transducers 130 it encloses, flow characteristic of the fluidwithin its internal volume, desired volume of the bladder extraneous tothe transducer sleeve, etc. The transducer sleeve 122 can becharacterized to be inelastic having a fixed expanded length, to berigid or to comprise a stiffening element, and in some embodiments thesleeve can be pressurized to higher pressure than other expandableportions.

Turning to FIG. 11, which is a side view simplified illustration of acatheter for ultrasonic-driven bladder therapeutic agent delivery inaccordance with some embodiments of the invention. As shown in theexemplary embodiment depicted in FIG. 11, during implementation, thegeometry of the catheter 150 protects the wall of the bladder fromcollapsing onto transducer sleeve 122. As shown in FIG. 11, a bladderwall tends to conform to the geometry of the catheter 10 forming a cone140 depicted in FIG. 11 by a phantom-line triangle 143. In someembodiments, tip 117 of catheter 150 forms an apex 141 of cone 140 and abase 142 of cone 140 is formed at the maximal cross-sectional area ofthe proximal balloon 124 at an inflated state. In this configuration,the wall of the bladder is prevented from collapsing onto and contactingtransducer sleeve 122 at an inflated state. This constraint can bedriven for example by a requirement to maintain a distance between thetransducer sleeve walls and the enclosed transducer e.g. in case thebladder surface collapses and engages the sleeve 122, to avoid bendingof the sleeve, etc. In some embodiments a diameter D110 of proximalballoon 124 is between 20 mm and 50 mm at an expanded state. In someembodiments, a diameter D110 of proximal balloon 124 is between 30 mmand 38 mm at an expanded state. In some embodiments, a diameter D120 ofa transducer sleeve 122 is between 5 mm and 20 mm. In some embodiments,a diameter D120 of a transducer sleeve 122 is between 8 mm and 17 mm. Insome embodiments, a diameter D120 of a transducer sleeve 122 is between12 mm and 14 mm. In some embodiments a length L130 of the transducersleeve is between 5 and 50 mm at an expanded state. In some embodimentsa length L130 of the transducer sleeve is between 15 and 40 mm at anexpanded state.

In some embodiments, catheter 150 can comprise two distinct balloonssuch as shown, for example, in FIGS. 8 to 12. In some embodiments,different pressures or different pressuring fluids can be used for theexpansion of the proximal balloon 124 and the transducer sleeve 122portions. In some embodiments, only portions of the wall of balloon 124are elastically inflatable, while other portions are inelastic.

In some embodiments, a method for deployment of the ultrasonic-drivencatheter according to some embodiments of the invention includes:

-   -   Inserting catheter 110 into bladder 100 through urethra 103        until the distal end 117 engages the bladder distal (opposing        the trigone) internal surface 105;    -   Expanding balloon 124 and the transducer sleeve 122 to a        pre-determined pressure or volume by a pressurized acoustic        fluid and maintaining all expanded portions at an expanded        state;    -   Draining the bladder 100 through therapeutic fluid port(s) 116;    -   Washing the bladder by inserting saline and draining the saline        through port(s) 116;    -   Mixing therapeutic fluid with gassed liquid as described        elsewhere herein (this step can be optional or performed any        time prior or during the deployment of the catheter); and    -   Providing a therapeutic fluid through therapeutic fluid port(s)        116.

In some embodiments, a method for treatment of a bladder wall using anultrasonic-driven catheter according to some embodiments of theinvention includes:

-   -   Fixing catheter 110 within bladder 100 by ensuring expanded        balloon 124 engages the proximal wall (trigone area) 105′ of the        bladder;    -   According to some embodiments of the invention, circulating the        acoustic fluid within the transducer portion 122 by supplying        fluid via a first fluid port 115 a and removing acoustic fluid        via a second fluid port 115 b; and    -   Activating the transducer 130.

In some embodiments, the ultrasonic-driven treatment performed by thecatheter 110 inserted within a bladder 100 is terminated by thefollowing method, according to some embodiments of the invention:

-   -   Inactivating the operation of transducer 130;    -   Removing therapeutic fluid via therapeutic fluid ports 116;    -   Inserting saline on bladder surface 105 through ports 116 (e.g.        to clean the bladder).    -   Collapsing expanded portions 124, 122 by releasing or evacuating        the acoustic fluid via the acoustic fluid ports 114, 115 a and        115 b; and    -   Withdrawing catheter 110 out of the bladder 100 through urethra        103.

In accordance to some embodiments of the invention, the deployment ofthe catheter for ultrasonic-driven treatment of a bladder wall andtreatment is carried out within the bladder, by the following method:

-   -   Inserting catheter 110 into bladder 100 through a urethra 103;    -   Expanding balloon 124 and the transducer sleeve 122, to a        pre-determine pressure or volume by a pressurized acoustic fluid        (e.g. 20-40 cc of fluid) and keeping expanded balloon 124 and        transducer sleeve 122 at an expanded state;    -   Draining the bladder of fluid through therapeutic fluid port(s)        116;    -   Supplying saline through therapeutic fluid port(s) 116;    -   Supplying a gassed liquid as described elsewhere herein through        bladder therapeutic fluid port(s) 116;    -   Activating the transducer 130;    -   Inactivating transducer 130;    -   Draining the bladder 100 of gassed fluid through therapeutic        fluid port(s) 116;    -   Supplying a therapeutic fluid (e.g. 20-40 cc) through        therapeutic fluid port(s) 116.

In some embodiments of the catheter for ultrasound-driven treatment of abladder, at least one of the expandable portions at an expanded state isshaped as at least one of a sphere, a spheroid or a toroid. In someembodiments, at least one of the expandable portions at an expandedstate comprises a C-shaped cross-section. In some embodiments, at leastone of the expandable portions at an expanded state comprises anumbrella configuration.

For example, FIG. 12 shows an embodiment in which the expandable portion824 is toroidal in geometry. In some embodiments, catheter 811 comprisesa therapeutic fluid port 816 between a transducer sleeve 822 and theexpandable portion 824. In the exemplary embodiment shown in FIG. 12,toroidal expandable portion 824 when inflated, expands distally, alongcatheter tube 811 towards tip 802 as indicated by arrows 850 anddirecting any therapeutic fluid supplied via therapeutic fluid port 816into treatment volume 807 to surround transducer 830 thus increasingtreatment efficacy.

A potential advantage in this configuration is in that the treatmentarea is more limited and therefore defined more accurately and that alower amount of therapeutic fluid is required to treat a given area ofbladder wall limiting waste of therapeutic fluid.

Shaping of any of the balloons can done by: molding, differentialthickness, varying materials, integral elements, etc. Another method forshaping any of the balloon portions can be by limiting its expansion byexternal elements, such as a sleeve or a net.

In some embodiments, the catheter for ultrasound-driven treatment of abladder is configured to comprise energy supply conduits for theultrasound transducer 30/130/830. Additionally, in some embodiments, thecatheter for ultrasound-driven treatment of a bladder comprises one ormore thermocouples disposed within one or more of the expandableportions. In some embodiments, the thermocouple is configured to measurefluid temperature within the treatment volume. In some embodiments, oneor more thermocouples are configured to measure temperature of thebladder wall tissue to prevent overheating of the wall of the bladder.In some embodiments, one or more of the thermocouples are coupled to thebladder wall. In some embodiments, the thermocouple is configured tomeasure fluid temperature within one or more of the expandable portionsand/or the transducer sleeve. In some embodiments, the thermocouple isconfigured to measure temperature over the surface of the transducer. Insome embodiments, the catheter for ultrasound-driven treatment of abladder comprises one or more pressure sensors within at least one ofthe expandable portions configured to monitor fluid pressure within theexpandable portion. In the exemplary embodiments illustrated in FIGS. 1and 4, the transducers 30/130 are cylindrical. However, in otherembodiments, the transducer can be flat. In some embodiments,transducers 30/130 are mounted on the tube 11/111 by spacers 32/132 and33/133. Fixation of the transducer at a pre-determined location on thetube provides predictable and repeatable energy parameters.

In some embodiments, the spacers 32/132 and 33/133 are configured tosupport the transducers elevated from tube 11/111, so to form a gapbetween the transducer and the tube 11/111. In some embodiments the gapis in the range between 0.05 mm and 4 mm. In some embodiments the gap isin the range between 0.1 mm and 2.5 mm. In some embodiments, the gap isfilled by acoustic fluid flowing within the enclosing transducer sleeve22/122, which can result in cooling of the transducer. In someembodiments, the gap is filled by acoustic fluid which flows within thetransducer sleeve 22/122, thereby transferring heat form the transducer.

In some embodiments, the one or more of the spacers 32/33/132/133 ismounted on the tube 11/111. In some embodiments, the transducer 30/130is mounted on one or more of the spacers 32/33/132/133. In someembodiments, a transducer 30/130 is positioned onto one spacer32/33/132/133. In some embodiments, the transducer 30/130 is positionedon a plurality of spacers 32/33/132/133. In some embodiments, the lengthof the spacer 32/33/132/133 is larger than the outermost radius of thespacer 32/33/132/133. In some embodiments, the length of the spacer isat least 50% of the length of the transducer 30/130. In someembodiments, the length of the spacer 32/33/132/133 is up to 30% of thelength of the transducer 30/130.

In some embodiments, the spacer 32/33/132/133 adds concentricity,electrical protection, and mechanical scaffold to the catheter forultrasonic-driven bladder drug delivery. In some embodiments, distancingthe transducer from the catheter and/or tube provides electricalinsulation by having an isolation medium (e.g., air) between thetransducer and the catheter.

Turning to FIGS. 13 and 14, which are simplified illustrations of sideviews of a catheter for ultrasonic-driven bladder drug delivery, inaccordance with some embodiments of the present disclosure. As shown inFIGS. 13 and 14, normally open stents, e.g. expandable stents 224, 324,326, replaces at least some of expandable portions disclosed in thepreceding embodiments, such as 24, 26, 124, can be replaced by normallyopen stents, e.g. expandable stents 224, 324, 326. Each of the stents224, 324, 326 are configured as normally open and remains enclosedwithin a stent sleeve (not shown) prior to inserting the catheter210/310 into a bladder. The stents are configured to open upon exposingout of the stent sleeve and to engage the bladder wall. Any of thestents can have a fluid sealing surface to block fluid within a bladdercavity volume defined within the bladder on one side of the sealingsurface to flow into a bladder cavity volume defined on an opposite sideof the stent sealing surface.

In the embodiments illustrated in FIGS. 1 and 8, the transducers arefixed to the tube by spacers (e.g. 32/132 and 33/133). The fixation ofthe transducer at a pre-determined location and centralized around thetube, helps providing predictable and repeatable energy parameters. Thespacers support the transducers, such that a gap is defined between thetransducer and the tube. In some embodiments, the gap is in the range of0.05 to 4 mm. In some embodiments, the gap is in the range of 0.1 to 2.5mm. In some embodiments, the gap is filled by an acoustic fluid whichflows within the enclosing transducer sleeve 22/122/222/322822, therebycooling the transducer.

In some embodiments, at least one of stents 224, 324, 326 is replaceableby a balloon. In some embodiments, the catheter for ultrasonic-drivenbladder drug delivery comprises at least one balloon, at least onestent, or any combination thereof.

The following are some examples of treatment parameters that enable aneffective and safe treatment, according to some embodiments of theinvention:

In some embodiments, the ultrasound transducer is between 100-400 Khz.In some embodiments, the ultrasound transducer is between 125-350 Khz.In some embodiments, the ultrasound transducer is between 150-300 Khz.

In some embodiments, the ultrasound transducer duty cycle is between5-50%. In some embodiments, the ultrasound transducer duty cycle isbetween 7-45%. In some embodiments, the ultrasound transducer duty cycleis between 10-40%.

In some embodiments, the ultrasound Isppa intensity is between 5-60W/cm2. In some embodiments, the ultrasound Isppa intensity is between8-55 W/cm2. In some embodiments, the ultrasound Isppa intensity isbetween 10-50 W/cm2.

The bladder distance from the ultrasound transducer ranges between 1-30mm

In some embodiments, the total treatment time in which the transducer isin use ranges between 5-30 minutes. In some embodiments, the totaltreatment time in which the transducer is in use ranges between 10-25minutes. In some embodiments, the total treatment time in which thetransducer is in use ranges between 15-20 minutes.

In some embodiments, the acoustic fluid pressure ranges between 0.3 Mpato 2 Mpa. In some embodiments, the acoustic fluid pressure rangesbetween 0.5 Mpa to 1 MPa.

In some embodiments, 3-40 mL of fluid fill up the volume of thetransducer sleeve. In some embodiments, 5-20 mL of fluid fill up thevolume of the transducer sleeve. In some embodiments, 10-14 mL of fluidfill up the volume of the transducer sleeve.

In some embodiments, 3-100 mL of fluid fill up the volume of at leastone expandable portion 24/26/124/824. In some embodiments, 10-70 mL offluid fill up the volume of at least one expandable portion24/26/124/824. In some embodiments, 30-55 mL of fluid fill up the volumeof at least one expandable portion 24/26/124/824.

In some embodiments, 5-300 mL of fluid is streamed into the bladdervolume. In some embodiments, 15-100 mL of fluid is streamed into thebladder volume. In some embodiments, 25-50 mL of fluid is streamed intothe bladder volume.

Gas bubbles in liquid serve as nucleation seeds for the generation ofcavitation. Therefore, increasing the amount of gas bubbles in thetherapeutic fluid increases the efficiency of the ultrasound treatment.

Additionally, ultrasound transducers introduced into the bladder arecommonly limited in the level of energy they can emit. Additionally, thefluid medium partially blocks and/or slows down ultrasound wavestraveling from the transducer towards the bladder wall, thereby exposingthe bladder wall to energy which may be insufficient for driving thetreatment agent onto the tissue. Hence, to achieve efficacious treatmentof a bladder wall, the ultrasound transducer needs to be activated inclose proximity to the bladder wall, which increases the risk of damageto the wall tissue due to exposure to excessive heat generated from thetransducer.

Introduction of nucleation seeds, such as solid particles, semi-solids,micro-bubbles, and the like, in the therapeutic fluid distributes gasbubbles throughout the fluid. The gas bubbles closer to the transducerabsorb a portion of the ultrasound radiation by forming cavitation,however the presence of gas bubbles throughout the treatment volume andespecially in proximity to the bladder wall enables their activation(i.e., production of cavitation) even by the low energy ultrasound wavesthat would be ineffective in the absence of the nucleation seeds.Dispersing of the cavitation in the therapeutic fluid allows cavitationthroughout the therapeutic fluid and not only in the layer encounteredby ultrasound emitted waves in the immediate surroundings of thetransducer sleeve.

The presence of these bubbles therefore reduces the energy thresholdrequired for cavitation generation. This allows using less acousticenergy, thus making the treatment safer to tissues. In some embodiments,increasing the amount of cavitation bubbles within the therapeutic fluidliquid is prepared by adding gassed sterile liquid, such as salinewithin the therapeutic agent.

In some embodiments of the present invention there is provided a methodfor increasing the amount of cavitation bubbles within the therapeuticfluid liquid including:

-   -   pressurizing a sterile liquid with a gas to generate a gassed        liquid;    -   maintaining the gassed liquid compressed for a predetermined        duration;    -   preparing a therapeutic fluid by releasing a therapeutic agent        (formed as a powder or a liquid) into the gassed liquid.

For example, in some embodiments, the gas is at least one of air,helium, nitrogen, oxygen, or any combination thereof. In someembodiments, the pressurizing of a sterile liquid with a gas is at apressure of 8 to 30 atmospheres. In some embodiments, the predeterminedduration is between 0.5-2 hours. In some embodiments, the predeterminedduration is 1 hour.

When adding the gassed liquid into the therapeutic fluid, theequilibrium of gases is swayed toward the therapeutic agent, therebyincreasing the gas content therein. When it decompresses (as pressure isimmediately released) within the therapeutic agent, the equilibrium ofgases is swayed back towards the surrounding atmosphere and the excessgas is released in the form of small bubbles. These small bubbles serveas cavitation nucleation sites during the treatment.

In some embodiments, the therapeutic fluid is mixed into the gassedfluid. in some embodiments, the gassed fluid is mixed into thetherapeutic fluid. in some embodiments, the gassed fluid is a diluentfor the therapeutic fluid.

Example 1

The following experiment was done to determine the efficacy oftreatments using catheter for ultrasonic-driven treatment of a bladdercompared to untreated tissue and gold standard 100 units Botox®intravesical injections.

Reference is made to FIG. 15, which is an exemplary chart of parametersof implementation of a catheter for ultrasonic-driven treatment of abladder, in accordance with some embodiments of the invention. thefollowing experiment was tested on 8 pigs.

In the present example, the ultrasonic-driven treatment of the bladderby implementation of the catheter for ultrasonic-driven treatment of abladder begins by application of local anesthesia to the bladder 1.Next, the catheter 10 is inserted at step 1400 into bladder 1 through aurethra 3 and the expandable portions 24, 26, and transducer sleeve 22are expanded at step 1420 by inflating 10-15 mL. In the present example,the bladder 1 is washed twice with saline by supplying at step 1440saline and then draining the bladder 1 at step 1430 through therapeuticfluid port(s) 17.

Next, 30 mL of therapeutic fluid is then instilled to the bladder, andthe expandable portions 24, 26, and transducer sleeve 22 are fullyinflated inside the bladder to 35 mL. A pump is started to circulateacoustic fluid within the expandable portions 24, 26, and transducersleeve 22. The transducer is switched on at a frequency of 200 kHz for15 minutes, and turned off, as depicted by FIG. 15. The duty cycle ofthe transduce is 15%. Lastly, the therapeutic fluid is incubated withinthe bladder post-treatment for 10 minutes, as depicted by FIG. 15.

In the present example, the therapeutic is botulinum toxin A (Botox®)solution in saline. The dose of the toxin is 100-200 units. In thisexample, the saline is normal sterile saline. In some embodiments, andin this example, the fluid is not gassed.

Additionally, 3 pigs were treated with the gold standard 100 unitsBotox® intravesical injections.

Pathological reports of the bladders, kidneys, urethras, ureters, andother organs were taken. Additionally, the efficacy of the treatments ofcatheter for ultrasonic-driven treatment of a bladder was compared tothe gold standard 100 units Botox® intravesical injections and to acontrol group of pigs which did not received any treatment was measuredby measuring the contractility of the detrusor muscle after eachtreatment.

Reference is made to FIG. 16, which is a graph of the contractility ofthe detrusor muscle after each treatment: treatments using catheter forultrasonic-driven treatment of a bladder compared to untreated tissue,and gold standard 100 units Botox® intravesical injections. Thecontractility of the detrusor muscle after each treatment as shown bythe y-axis is a percent ratio of the contractility after a treatment inrelation to the contractility of the detrusor muscle after receivingcarbachol (CCh). The contractility vs. CCh ratio depicts how much eachdetrusor muscle contracted in relation to a maximal contraction achievedby the CCh treatment.

In the graph of FIG. 16, 100% contractility vs. CCh is consistent withno Botox® activity whereas lower percent of muscle activity iscorrelated with Botox® administration. It is shown that shows that boththe treatments using catheter for ultrasonic-driven treatment and thegold standard 100 units Botox® intravesical injections achieved betterresults than the control group which was untreated, however, theefficacy of treatments using catheter for ultrasonic-driven treatment isat least the same or higher than the gold standard intravesicalinjections treatment.

For example, at a frequency of 8 Hz, the bladders which receivedtreatment using the catheter had a contractility vs. CCh ratio of about39%, whereas the bladders which received the intravesical injections hada contractility vs. CCh ratio of about 44%, and the control group was atabout 61%.

At a frequency of 32 Hz, the bladders which received treatment using thecatheter had a contractility vs. CCh ratio of about 78%, whereas thebladders which received the intravesical injections had a contractilityvs. CCh ratio of about 82%, and the control group was at 100%.

Example 2

The following experiment was done to determine the efficacy oftreatments using catheter for ultrasonic-driven treatment of anOveractive bladder (OAB) in human patients. The parameters ofimplementation for the catheter for ultrasonic-driven treatmentcorrespond to the table depicted by FIG. 16 and the parameters of thetreatment in pigs shown in Example 1. Ten humans were treated andobserved for 14 days post procedure.

Results of the treatment in humans' bladders using the catheter forultrasonic-driven treatment showed no adverse events, serious ornon-serious. Additionally, specific data of bladder function wasobtained from two patients pre and post procedure.

Patients suffering from an overactive bladder experience sudden urges tourinate and frequent urinations during both day and night, caused byinvoluntary contractions by the detrusor muscle.

Reference is made to FIG. 17, which is a table of efficacy data from twohuman patients comparing pre-procedure bladder function to 14 days postprocedure bladder function. As shown in FIG. 17, the average volume ofeach micturation increased by 22% and 27% for patients 3002 and 3004,respectively. Increase in the volume of each micturation is indicativeof more urine filling up the bladder of the patient before urination.Additionally, the average number of nocturnal urinations has decreasedby 60% and 10% for patients 3002 and 3004, respectively, whichcorresponds to the increase in volume of each micturation. An increasein the volume of each micturation decreases the number of times apatient needs to urinate.

As shown in FIG. 17, the average number of urinary incontinence forpatient 3004 decreased by 62.5%. patient 3002 experienced no change inthe average number of urinary incontinence. The decrease of number ofurinary incontinence shows the efficacy of the treatment using thecatheter for ultrasonic-driven treatment in human patients sufferingfrom OAB.

Lastly, post procedure OAB-q (14 days post-procedure) were compared topre-procedure OAB-q of patients 3002 and 3004, showing a decrease of4.1% and 38.6%, respectively. The decrease of the OAB-q scores indicatesan increase in general wellbeing and decrease in severity of symptoms ofOAB.

Throughout this application, various embodiments of this invention maybe presented in a range format. It should be understood that thedescription in range format is merely for convenience and brevity andshould not be construed as an inflexible limitation on the scope of theinvention. Accordingly, the description of a range should be consideredto have specifically disclosed all the possible subranges as well asindividual numerical values within that range. For example, descriptionof a range such as from 1 to 6 should be considered to have specificallydisclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numberswithin that range, for example, 1, 2, 3, 4, 5, and 6. This appliesregardless of the breadth of the range.

Whenever a numerical range is indicated herein, it is meant to includeany cited numeral (fractional or integral) within the indicated range.The phrases “ranging/ranges between” a first indicate number and asecond indicate number and “ranging/ranges from” a first indicate number“to” a second indicate number are used herein interchangeably and aremeant to include the first and second indicated numbers and all thefractional and integral numerals therebetween.

In the description and claims of the application, each of the words“comprise” “include” and “have”, and forms thereof, are not necessarilylimited to members in a list with which the words may be associated. Inaddition, where there are inconsistencies between this application andany document incorporated by reference, it is hereby intended that thepresent application controls.

The descriptions of the various embodiments of the present inventionhave been presented for purposes of illustration, but are not intendedto be exhaustive or limited to the embodiments disclosed. Manymodifications and variations will be apparent to those of ordinary skillin the art without departing from the scope and spirit of the describedembodiments. The terminology used herein was chosen to best explain theprinciples of the embodiments, the practical application or technicalimprovement over technologies found in the marketplace, or to enableothers of ordinary skill in the art to understand the embodimentsdisclosed herein.

What is claimed is:
 1. A catheter for ultrasonic-driven bladdertherapeutic agent delivery, comprising: a tube having (ii) one or moreexpandable portions, wherein at least one of said one or more expandableportions is a proximal expandable portion and (ii) a distal end; and atleast one transducer sleeve accommodating at least one ultrasoundtransducer mounted on said tube between said proximal expandable portionand said distal end.
 2. A catheter according to claim 1, wherein saidproximal expandable portion is expandable inside a bladder from acontracted state to an expanded state in which said expandable portionis urged against the bladder wall to form a sealed volume within thebladder between said expandable portion and a trigone area of saidbladder.
 3. A catheter according to claim 1, comprising at least oneadditional expandable portion, wherein said transducer sleeve isdisposed between said proximal expandable portion and said at least oneadditional expandable portion.
 4. A catheter according to claim 1,wherein the transducer sleeve and at least one of the one or moreexpandable portions are in fluid communication.
 5. A catheter accordingto claim 1, wherein the maximal cross-sectional area of the transducersleeve at an expanded state thereof is smaller than the maximalcross-sectional area of any one of the one or more expandable portionsat least at their greatest circumference.
 6. A catheter according toclaim 1, wherein at least one of the tube and transducer are concentricwith at least one of the one or more expandable portions.
 7. (canceled)8. A catheter according to claim 1, wherein the tube comprises at leastone fluid port located within a lumen of at least one of the one or moreexpandable portions.
 9. A catheter according to claim 1, wherein thetube comprises at least two fluid ports in fluid communication with thelumen of said transducer sleeve and wherein fluid flow is maintainedbetween said ports, and wherein said transducer is positioned betweensaid ports.
 10. (canceled)
 11. A catheter according to claim 1, whereinthe tube comprises at least one therapeutic fluid port along its lengththat opens to a lumen of a bladder.
 12. A catheter according to claim 1,further comprising a blind tip at said distal end, wherein said at leastone therapeutic fluid port is positioned along the circumference of thetip.
 13. A catheter according to claim 1, wherein the transducer iselevated from a surface of the tube so as to define a gap between thetransducer and the surface of the tube.
 14. A catheter according toclaim 1, further comprising at least one spacer positioned on said tubeand wherein said transducer is mounted on said at least one spacer. 15.(canceled)
 16. (canceled)
 17. A catheter according to claim 1, whereinthe at least one of the one or more expandable portions is one of:toroidal and spheroid.
 18. (canceled)
 19. (canceled)
 20. (canceled) 21.A method for treating a bladder using a catheter for ultrasonic-drivenbladder therapeutic agent delivery comprising: inserting a distalexpandable portion of the catheter into the bladder via a urethra;expanding the expandable portion; supplying therapeutic fluid into thebladder through at least one therapeutic fluid port in the catheter;advancing the catheter in the bladder and inserting a proximalexpandable portion of the catheter into the bladder; expanding theproximal expandable portion and trapping the therapeutic fluid betweenthe distal expandable portion and the proximal expandable portion; andforming cavitations in the therapeutic fluid.
 22. The method accordingto claim 21, wherein supplying the therapeutic fluid through a portbetween the one or more expandable portions.
 23. (canceled)
 24. A methodfor treating a bladder using a catheter for ultrasonic-driven bladdertherapeutic agent delivery comprising: inserting a distal expandableportion of the catheter into the bladder via a urethra; supplying fluidinto the bladder through at least one fluid port in the catheter;emitting ultrasound energy and forming cavitations in the gassed fluid;draining the bladder content; and supplying therapeutic fluid into thebladder through at least one therapeutic fluid port in the catheter. 25.The method according to claim 24, further comprising expanding a distalexpandable portion of the catheter prior to said supplying of saidtherapeutic fluid into the bladder.
 26. (canceled)
 27. (canceled) 28.The method according to claim 25, wherein the method comprises stoppingsaid emitting of said ultrasound energy during the draining of thebladder content and/or the supplying of the therapeutic fluid into thebladder through the at least one therapeutic fluid port in the catheter.29. The method according to claim 25, wherein the method comprisesadvancing a proximal expandable portion prior to said emitting of saidultrasound energy.
 30. The method according to claim 25, wherein themethod comprises expanding a proximal expandable portion prior to saidemitting of said ultrasound energy.